WO2022143976A1 - Phenylarsine oxide crystal form i, crystal form ii, and crystal form iii and preparation method therefor - Google Patents

Abstract

The present invention provides a crystal form I, a crystal form II, and a crystal form III of a compound represented by formula (I). The phenylarsine oxide crystal form I, crystal form II, and crystal form III of the present invention have good high temperature stability, high humidity stability and illumination stability, which are beneficial to the use of the crystal form I, the crystal form II, and the crystal form III in pharmaceutical processing and pharmaceutical compositions.

Description

Benzene arsenic oxide crystal form I, crystal form II and crystal form III and preparation method thereof technical field

The present invention relates to various crystal forms of phenylarsenic oxide as a PI4KIIIα protein inhibitor, in particular, to phenylarsenic oxide crystal form I, crystal form II and crystal form III and a preparation method thereof.

Background technique

Phenylarsine Oxide (PAO) is a known bioinhibitor, and the arsenic atom in this molecule has a high affinity for the sulfur atom of the sulfhydryl group in biomolecules. Recent studies have found that arsenic oxide is a PI4KIIIα inhibitor that can be used to treat Alzheimer's disease.

However, the crystal form of phenylarsenic oxide is not disclosed in the prior art, and the solid phenylarsenic oxide usually exists in an amorphous state. As known to those skilled in the art, although amorphous has higher solubility and dissolution rate than crystalline form in most cases, it is unstable, has strong hygroscopicity and is prone to crystal form transformation. Therefore, amorphous has problems of processing stability and storage stability, and in the production process, the bulk density of amorphous particles is small, the surface free energy is high, and it is easy to cause a series of preparations such as agglomeration, poor fluidity, and strong elastic deformation. The problem seriously affects the clinical value of amorphous benzene arsenic oxide.

As we all know, the bioavailability of the same drug with different crystal forms may also be different. In addition, its stability, fluidity, and compressibility may also be different. These physical and chemical properties have a certain impact on the application of the drug, thereby affecting the efficacy of drugs. Therefore, there is a need for crystalline forms of arsenic phenylene oxide with superior physiochemical properties that can be advantageously used in pharmaceutical processing and pharmaceutical compositions. The crystal form I, crystal form II and crystal form III of the benzene arsenic oxide developed by the invention have excellent stability.

SUMMARY OF THE INVENTION

The problem to be solved by the present invention is to provide a stable arsenic oxide crystal form, improve its bioavailability, be beneficial to the application in solid medicine, and provide more qualitative and quantitative information for the research on the curative effect of solid medicine.

In order to solve the above-mentioned technical problems, the first aspect of the present invention provides a new crystal form of phenylarsenic oxide, more specifically, a phenylarsenic oxide crystal form I (hereinafter sometimes referred to as a compound represented by formula (I) for short) The crystal form I, "PAO crystal form I" or "crystal form I") is characterized in that its X-ray powder diffraction (XRPD) pattern has diffraction peaks at the following 2θ angles: 8.02°±0.2°, 8.83°±0.2 °, 9.38°±0.2°, 11.57°±0.2°, 17.92°±0.2°, 18.36°±0.2°, 19.89°±0.2°, 21.21°±0.2°, 22.62°±0.2°, 26.40°±0.2°, The 2θ value error range is ±0.2° or ±0.15°.

Further, the XRPD pattern of benzene arsenic oxide crystal form I has diffraction peaks at the following 2θ angles: 8.02°±0.2°, 8.83°±0.2°, 9.38°±0.2°, 11.57°±0.2°, 17.92°±0.2 °, 18.36°±0.2°, 19.89°±0.2°, 21.21°±0.2°, 21.68°±0.2°, 22.62°±0.2°, 25.27°±0.2°, 26.40°±0.2°, 29.50°±0.2°, 30.33°±0.2°, 32.49°±0.2°, and the 2θ value error range is ±0.2° or ±0.15°.

According to the crystal form I of benzene arsenic oxide of the present invention, the XRPD pattern of the crystal form is basically as shown in FIG. 1 .

The crystal form I of benzene arsenic oxide according to the present invention has at least one of the following features: a DSC spectrum, a TGA spectrum and a dynamic moisture adsorption spectrum that are substantially the same as those of FIGS. 2-4 in the accompanying drawings.

The invention provides a preparation method of benzene arsenic oxide crystal form I, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent to obtain a suspension, which is suspended at room temperature;

(2) Collect the solids in the suspension, namely the benzene arsenic oxide crystal form I solid.

In the above preparation method of phenylarsenic oxide crystal form I, the solvent is selected from water, methanol, acetone, isopropyl acetate, acetonitrile, 4-methyl-2-pentanone, n-heptane, methyl tert-butyl The group consisting of ether, isopropyl ether, tetrahydrofuran, ethyl acetate and mixtures of any two or more thereof. More preferably, the solvent is water, methanol-water, acetone, isopropyl acetate-acetone, acetonitrile, 4-methyl-2-pentanone-acetonitrile, n-heptane, methyl tert-butyl ether, or isopropyl acetate Propyl ether-tetrahydrofuran. In a preferred preparation method, the suspension time is 1 day, 2 days, 3 days, 5 days, 7 days, 10 days or 14 days.

The invention provides another preparation method of benzene arsenic oxide crystal form I, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent to obtain a solution;

(2) Naturally volatilize the solvent of the solution at room temperature, and collect the solid, which is the benzene arsenic oxide crystal form I solid.

In the above-mentioned preparation method of phenylarsenic oxide crystal form I, the solvent is selected from the group consisting of ethyl acetate, dichloromethane, N,N-dimethylformamide, n-heptane and any two or more mixtures thereof. Group. More preferably, the solvent is ethyl acetate, dichloromethane or N,N-dimethylformamide.

The invention provides another preparation method of phenylarsenic oxide crystal form I, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

(2) Transfer the hot solution to a low temperature environment for cooling, and collect the precipitated solid, which is the benzene arsenic oxide crystal form I solid.

In the above-mentioned preparation method of phenylarsenic oxide crystal form I, the solvent is selected from isopropanol, acetone, ethyl acetate, isopropyl acetate, n-butanol, acetonitrile, 4-methyl-2-pentanone, The group consisting of heptane, cyclohexane, methyl tert-butyl ether, isopropyl ether, dichloromethane, 1,4-dioxane or 2-methyltetrahydrofuran and mixtures of any two or more thereof. More preferably, the solvent is isopropyl acetate, acetonitrile or 2-methyltetrahydrofuran-ethyl acetate. The heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C. The low temperature environment temperature is not lower than the melting point of the solvent, preferably -30 to 0°C.

The invention provides another preparation method of benzene arsenic oxide crystal form I, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

(2) The hot solution is slowly cooled in a controlled manner until the solid is precipitated, and the precipitated solid is collected, which is the benzene arsenic oxide crystal form I solid.

In the above preparation method of phenylarsenic oxide crystal form I, the solvent is selected from the group consisting of water, acetone, isopropyl acetate, cyclohexane, acetonitrile, ethyl acetate and any two or more mixtures thereof. More preferably, the solvent is water or acetone-acetonitrile. The heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C. Preferably, the rate of controlled cooling is 5-10°C/h; the temperature is lowered to room temperature, close to 0°C or lower than 0°C.

The second aspect of the present invention provides a new crystal form of benzene arsenic oxide, more specifically, benzene arsenic oxide crystal form II (hereinafter sometimes also referred to as "crystal form II of the compound represented by formula (I)" , "PAO crystal form II" or "crystal form II"), characterized in that the XRPD pattern of the crystal form has diffraction peaks at the following 2θ angles: 8.48°±0.2°, 9.44°±0.2°, 14.63°± 0.2°, 15.83°±0.2°, 17.28°±0.2°, 24.90°±0.2°, 25.18°±0.2°, 25.89°±0.2°, 26.20°±0.2°, 31.40°±0.2°, among which 2θ value error range is ±0.2° or ±0.15°.

Further, the XRPD pattern of benzene arsenic oxide crystal form II has diffraction peaks at the following 2θ angles: 8.48°±0.2°, 9.44°±0.2°, 12.38°±0.2°, 13.00°±0.2°, 14.63°±0.2° , 15.83°±0.2°, 17.28°±0.2°, 19.90°±0.2°, 20.36°±0.2°, 24.90°±0.2°, 25.18°±0.2°, 25.89°±0.2°, 26.20°±0.2°, 31.40 °±0.2°, 32.84°±0.2°, where the 2θ value error range is ±0.2° or ±0.15°.

According to the crystal form II of benzene arsenic oxide of the present invention, the XRPD pattern of the crystal form is basically as shown in FIG. 6 .

The crystal form II of benzene arsenic oxide according to the present invention has at least one of the following features: a DSC spectrum, a TGA spectrum and a dynamic moisture adsorption spectrum that are substantially the same as those of FIGS. 7-9 in the accompanying drawings.

The invention provides a preparation method of benzene arsenic oxide crystal form II, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent to obtain a solution;

(2) Naturally volatilize the solvent of the solution at room temperature, and collect the solid, which is the benzene arsenic oxide crystal form II solid.

In the above preparation method of phenylarsenic oxide crystal form II, the solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclic The group consisting of hexane, isopropyl ether, 1,4-dioxane, toluene, n-heptane and mixtures of any two or more thereof. More preferably, the solvent is methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclohexane, isopropyl ether or 1,4 -Dioxane.

The invention provides another preparation method of benzene arsenic oxide crystal form II, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent to obtain a suspension, which is stirred and suspended at room temperature;

(2) The solid in the suspension is collected, which is the benzene arsenic oxide crystal form II solid.

In the above-mentioned preparation method of phenylarsenic oxide crystal form II, the solvent is the group consisting of methyl ethyl ketone, ethanol, cyclohexane, isopropanol, ethyl acetate and any two or more mixtures thereof. More preferably, the solvent is methyl ethyl ketone-ethanol-cyclohexane-isopropanol. In a preferred preparation method, the suspension time is 1 day, 2 days, 3 days, 5 days, 7 days, 10 days or 14 days.

The invention provides another preparation method of phenylarsenic oxide crystal form II, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

(2) Transfer the hot solution to a low temperature environment for cooling, and collect the precipitated solid, which is the benzene arsenic oxide crystal form II solid.

In the above preparation method of phenylarsenic oxide crystal form II, the solvent is selected from methanol, ethanol, isopropanol, n-butanol, methyl ethyl ketone, cyclohexane, dichloromethane, acetone, ethyl acetate, 4-methyl - The group consisting of 2-pentanone, cyclohexane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, and mixtures of any two or more thereof. More preferably, the solvent is methanol, ethanol, isopropanol-n-butanol, methyl ethyl ketone-cyclohexane, dichloromethane, or n-butanol-methanol. The heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C. The low temperature environment temperature is not lower than the melting point of the solvent, preferably -30 to 0°C.

The invention provides another preparation method of benzene arsenic oxide crystal form II, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

(2) The hot solution is slowly cooled in a controlled manner until the solid is precipitated, and the precipitated solid is collected, which is the benzene arsenic oxide crystal form II solid.

In the above preparation method of phenylarsenic oxide crystal form II, the solvent is selected from ethanol, isopropanol, methyl ethyl ketone, isopropyl ether, acetonitrile, dichloromethane, methyl tert-butyl ether, 4-methyl-2- The group consisting of pentanone, n-heptane, 1,4-dioxane, acetone, isopropyl acetate, cyclohexane, dioxane, and mixtures of any two or more thereof. More preferably, the solvent is ethanol, isopropanol, methyl ethyl ketone-isopropyl ether, acetonitrile, dichloromethane-methyl tert-butyl ether, 4-methyl-2-pentanone-isopropyl ether, n-heptane - cyclohexane, methyl tert-butyl ether-isopropyl ether, or 1,4-dioxane. The heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C. Preferably, the rate of controlled cooling is 5-10°C/h; the temperature is lowered to room temperature, close to 0°C or lower than 0°C.

The third aspect of the present invention provides a new crystal form of benzene arsenic oxide, more specifically, benzene arsenic oxide crystal form III (hereinafter sometimes also referred to as "crystal form III of the compound represented by formula (I)" , "PAO crystal form III" or "crystal form III"), characterized in that the XRPD pattern of the crystal form has diffraction peaks at the following 2θ angles: 8.39°±0.2°, 9.50°±0.2°, 16.04°± 0.2°, 16.56°±0.2°, 18.06°±0.2°, 19.11°±0.2°, 19.44°±0.2°, 23.85°±0.2°, 25.25°±0.2°, 25.70°±0.2°, 31.74°±0.2° , where the 2θ value error range is ±0.2° or ±0.15°.

Further, the XRPD pattern of benzene arsenic oxide crystal form II has diffraction peaks at the following 2θ angles: 8.39°±0.2°, 9.50°±0.2°, 12.55°±0.2°, 13.85°±0.2°, 14.55°±0.2° , 15.14°±0.2°, 16.04°±0.2°, 16.56°±0.2°, 18.06°±0.2°, 19.11°±0.2°, 19.44°±0.2°, 20.68°±0.2°, 22.06°±0.2°, 23.85 °±0.2°, 25.25°±0.2°, 25.70°±0.2°, 29.23°±0.2°, 32.10°±0.2°, 33.15°±0.2°, 33.69°±0.2°, 34.51°±0.2°, 36.75°± 0.2°, 39.00°±0.2°, 31.74°±0.2°, and the 2θ value error range is ±0.2° or ±0.15°.

According to the crystal form III of benzene arsenic oxide of the present invention, the XRPD pattern of the crystal form is substantially as shown in FIG. 11 .

The crystal form III of benzene arsenic oxide according to the present invention has at least one of the following features: a DSC spectrum, a TGA spectrum and a dynamic moisture adsorption spectrum that are substantially the same as those of FIGS. 12-14 in the accompanying drawings.

The invention provides a preparation method of benzene arsenic oxide crystal form III, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent to obtain a solution;

(2) at room temperature, the solvent of the solution is naturally volatilized, and the solid is collected, which is the phenylarsenic oxide crystal form III solid,

In the above preparation method of phenylarsenic oxide crystal form III, the solvent is toluene.

The invention provides another preparation method of benzene arsenic oxide crystal form III, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent to obtain a suspension, which is stirred and suspended under heating;

(2) Collecting the solid in the suspension, that is, the benzene arsenic oxide crystal form III solid.

In the above-mentioned preparation method of phenylarsenic oxide crystal form III, the solvent is selected from the group consisting of toluene, acetone, ethyl acetate and a mixture of any two or more thereof. More preferably, the solvent is acetone or ethyl acetate. In a preferred method of preparation, the suspension time is at least 1 day. The heating temperature is preferably 40 to 60°C, and more preferably 50°C.

The invention provides another preparation method of phenylarsenic oxide crystal form III, comprising the following steps:

(1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

(2) Transfer the hot solution to a low temperature environment for cooling, and collect the precipitated solid, which is the benzene arsenic oxide crystal form III solid.

In the above preparation method of phenylarsenic oxide crystal form III, the solvent is toluene. The heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C. The low temperature environment temperature is not lower than the melting point of the solvent, preferably -30 to 0°C.

It should be understood that those of ordinary skill in the art can adjust the amount of reagents used in the method of the present invention according to their knowledge and experience, including scaling up or reducing the amount of raw materials and adjusting the amount of solvent, and can change the temperature of the method of the present invention. These adjusted protocols are also included in the method of the present invention.

The phenylarsenic oxide crystal form I, crystal form II and crystal form III of the present invention all have excellent stability, which is beneficial to its pharmaceutical processing and use in pharmaceutical compositions, and can provide qualitative and quantitative information, which is useful for further It is of great significance to study the efficacy of such solid drugs.

Therefore, the fourth aspect of the present invention provides a pharmaceutical composition comprising any one of the phenylarsenic oxide crystal form I, crystal form II and crystal form III of the present invention or a combination thereof, and pharmaceutically acceptable excipients, preferably Typically, the pharmaceutically acceptable adjuvants are pharmaceutically acceptable carriers, diluents and/or excipients.

The fifth aspect of the present invention provides the use of any one of the crystal form I, crystal form II and crystal form III of phenylarsenic oxide of the present invention or a combination thereof or the pharmaceutical composition of the present invention in preparing a medicine.

In a specific embodiment, the medicament is for the treatment or prevention of Alzheimer's disease in a patient.

Description of drawings

Fig. 1 is the XRPD spectrum of benzene arsenic oxide crystal form I provided by the present invention.

Fig. 2 is the DSC spectrum of the benzene arsenic oxide crystal form I provided by the present invention.

Fig. 3 is the TGA spectrum of benzene arsenic oxide crystal form I provided by the present invention.

Fig. 4 is the DVS spectrum of benzene arsenic oxide crystal form I provided by the present invention.

Fig. 5 is the XRPD overlapping pattern of the stability test of the benzene arsenic oxide crystal form I provided by the present invention, from bottom to top are the control and 2 weeks of light, high temperature, high humidity and accelerated conditions.

Fig. 6 is the XRPD spectrum of the benzene arsenic oxide crystal form II provided by the present invention.

Fig. 7 is the DSC spectrum of the benzene arsenic oxide crystal form II provided by the present invention.

Fig. 8 is the TGA spectrum of the benzene arsenic oxide crystal form II provided by the present invention.

Fig. 9 is the DVS spectrum of the benzene arsenic oxide crystal form II provided by the present invention.

FIG. 10 is the XRPD overlapping pattern of the stability test of the benzene arsenic oxide crystal form II provided by the present invention.

Fig. 11 is the XRPD pattern of the benzene arsenic oxide crystal form III provided by the present invention.

Fig. 12 is the DSC spectrum of the benzene arsenic oxide crystal form III provided by the present invention.

FIG. 13 is the TGA spectrum of the benzene arsenic oxide crystal form III provided by the present invention.

FIG. 14 is the DVS spectrum of the benzene arsenic oxide crystal form III provided by the present invention.

Fig. 15 is the XRPD overlapping pattern of the stability test of the benzene arsenic oxide crystal form III provided by the present invention, from bottom to top, the control and 2 weeks of light, high temperature, high humidity and accelerated conditions.

Detailed ways

In the present invention, including the description and claims, unless otherwise specified, the following terms used have the following meanings:

The term "Alzheimer's disease" (AD) used in the present invention refers to an senile neurodegenerative disease with progressive learning and memory impairment as the prominent clinical symptom. Most AD patients have extracellular β-amyloid plaques in the middle and late stages, and intracellular neurofibrillary tangles composed of Tau protein, or loss of synapses and nerve cells. The disease can be present in both humans and non-human mammalian animals such as dogs.

The term "treating" as used herein means reversing, alleviating or inhibiting the progression of the disease to which the term applies, or one or more symptoms of the disease. As used herein, the term also includes prophylaxis of disease, including preventing the onset of the disease or any symptoms associated therewith, as well as reducing the severity of the disorder or any condition that precedes the onset, depending on the condition of the patient.

The term "patient" as used herein refers to an animal. Typically the animal is a mammal, for example also referring to primates such as humans (including adults and children, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish , birds, etc. In certain embodiments, the patient is a primate. In other embodiments, the patient is a human.

The term "comprising" used in the present invention is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

A crystal form may be considered in the present invention to be characterized by graphical data "depicted" by a graph. These data include, for example, powder X-ray diffraction patterns, Raman spectroscopy, Fourier transform-infrared spectroscopy, DSC curves and solid state NMR spectroscopy. The skilled artisan will appreciate that small changes in the graphical representation of such data (eg peak relative intensities and peak positions) may occur due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to the skilled artisan. Nonetheless, the skilled artisan is able to compare the pattern data in the figures herein with pattern data generated for an unknown crystal form, and can confirm whether the two sets of pattern data characterize the same crystal form.

"XRPD" refers to X-ray powder diffraction. "DSC" means Differential Scanning Thermal Analysis.

As used herein, the term "amorphous" or "amorphous form" is intended to mean that the substance, component or product in question lacks a characteristic crystalline shape or crystalline structure, is not substantially crystalline when determined, for example, by XRPD, or The substance, component or product in question, for example, is not birefringent when viewed using a polarized light microscope, or the X-ray powder diffraction pattern has no sharp peaks. In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free of other amorphous and/or crystalline forms.

As used herein, the terms "polymorph", "polymorphs", "crystal modification", "crystal form", "crystalline modification", "Polymorphic form" and "crystalline form" are understood to be synonymous and in the present invention refer to solid crystalline forms of compounds or complexes, including, but not limited to, single-component or multi-component Fractional crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts.

Polymorphs can be detected, identified, classified and characterized using techniques well known to those skilled in the art such as, but not limited to: Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), X-ray Powder Diffraction method (XRPD), single crystal X-ray diffraction method, vibrational spectroscopy, solution calorimetry, solid state nuclear magnetic resonance (SSNMR), Fourier transform-infrared spectroscopy (FT-IRspectrum) method, Raman spectroscopy (Ramanspectrum) method, thermal Stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility and dissolution rate. A crystal form can be described as the ability of a particular compound to crystallize in different crystal modifications while maintaining the same chemical structural formula. Polymorphs of a given substance are chemically equivalent, containing the same atoms bonded to each other in the same way, but in different crystalline forms that affect one or more physical properties, such as dissolution rate ), melting point, bulk density, stability, flow properties, etc. The graphical representation of such data may vary slightly (eg, peak relative intensities and peak positions) due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to those skilled in the art. Nonetheless, one skilled in the art can compare the pattern data in the figures herein with pattern data generated for an unknown crystal form, and can confirm whether the two sets of pattern data characterize the same crystal form.

Unless otherwise stated, when the text refers to spectra or data presented in graphical form (eg, XRPD, FT-IR, Raman, and NMR spectra), the term "peak" refers to a non-specific peak that can be recognized by one of ordinary skill in the art. Peaks or other special features caused by background noise.

As is well known in the field of X-ray powder diffraction (XRPD), for any given crystal form, the equipment used to obtain the X-ray powder diffraction (XRPD) pattern, humidity, temperature, orientation of powder crystals, and other parameters are all May cause some variability in the appearance, intensity and position of peaks in the diffractogram. See, for example, The United States Pharmacopeia #23, National Formulary #18, pp. 1843-1844, 1995. In the present case, the variability of ±0.2° 2Θ peak positions takes into account these possible variations without preventing unambiguous identification of the crystal forms shown. Identification of a crystalline form can be based on any unique difference peak (in °2Θ units) or a combination thereof, typically the more pronounced peaks. Accordingly, in some embodiments, crystalline compounds of the present invention are characterized by XRPD patterns having certain peak positions having substantially the same characteristics as the XRPD patterns provided in the accompanying figures of the present invention. Depending on the condition of the instrument used in this experiment, there may be an error tolerance of ±0.2° in the position of the diffraction peak.

The term "combination" means that a crystalline form contains its tautomer, ie the crystalline form is at least 60% pure, or at least 70% pure, or at least 80% pure, or at least 85% pure relative to its tautomer , or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% ; or means that one crystal form may contain another one or more crystal forms, that is, the purity of the crystal form relative to the other one or more crystal forms is at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or At least 99.9%; or it means that the crystal form contains other crystal forms, and the percentage of the other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

Whenever a number with a value of N is disclosed, any number with N±0.01, N±0.02, N±0.03, N±0.05, N±0.07, N±0.08, N±0.1, N±0.15, N±0.2, N ±1, N±1.5, N±2, N±3, N±4, N±5, N±6, N±7, N±8, N±9, N±10, the number of values will be explicitly Disclosure, where "±" means plus or minus. Whenever a lower limit, RL, and an upper limit, RU, in a numerical range are disclosed, any numerical value falling within that disclosed range is expressly disclosed.

Unless otherwise stated, percentages stated throughout this specification are weight/weight (w/w) percentages.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in the present invention, including any solvents, solid excipients, diluents, binders agents, disintegrating agents, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc. etc., suitable for the unique target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, synthesizes the contents of the documents herein, showing that different excipients can be used in the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except to the extent that any conventional excipients are incompatible with the compounds of the present invention, such as any adverse biological effect or interaction in a detrimental manner with any other component of a pharmaceutically acceptable composition, their Use is also contemplated by the present invention.

Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphate; glycine; sorbic acid; Potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; Vinylpyrrolidones; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxylate Sodium methylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents ; Coatings; Sweeteners; Flavourings; Perfumes; Preservatives and Antioxidants.

The crystalline compound of the present invention will be applied to, but in no way limited to, using an effective amount of the crystalline compound or pharmaceutical composition of the present invention to be administered to a patient to prevent or treat Alzheimer's disease in a patient, or to alleviate Alzheimer's disease symptoms, or slow the progression or onset of Alzheimer's. An "effective amount", "therapeutically effective amount" or "effective dose" of a crystalline compound or pharmaceutically acceptable pharmaceutical composition of the present invention refers to an amount that treats or lessens the severity of one or more of the disorders referred to in the present invention. effective amount. The crystalline compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide range of dosages. Can be divided into one or several doses. The methods, crystalline compounds and pharmaceutical compositions according to the present invention may be used in any amount and by any route of administration to be effective for treating or reducing the severity of a disease. The exact amount necessary will vary from patient to patient depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like.

Hereinafter, the present invention will be described in detail based on the embodiments and in conjunction with the accompanying drawings. The above aspects of the present invention and other aspects of the present invention will be apparent from the following detailed description. The scope of the present invention is not limited to the following examples. The benzene arsenic oxide raw material used in all embodiments of the present invention is the applicant (inventor) self-synthesis (F.F.Blicke and F.D.Smith.The action of aromatic Grignard reagents on arylarsine oxides. Journal of the American Chemical Society 1929, Volume 51, Issue 11, 3479-3483.; Nicholas C. Lloyd, Hugh W. Morgan, Brian K. Nicholson, Ron S. Ronimus. Substituted phenylarsonic acids; structures and spectroscopy. Journal of Organometallic Chemistry 2008, Volume 693, Issue 14, 2443-2450 .)

Characterization method:

X-ray powder diffraction

The measurement of the X-ray powder diffraction (XRPD) pattern was carried out using a D8 ADVANCE powder X-ray diffractometer from BRUKER. The light source was CuK, the X-ray intensity was 40kV/40mA, the scanning mode was Theta-theta, the scanning angle (2θ) ranged from 4° to 40°, the step size was 0.05°, and the scanning speed was 0.5 sec/step. Samples were processed by pressing glass slides directly on the test plate.

Differential Scanning Calorimetry

Differential Scanning Calorimetry (DSC) was performed using a TA Instruments Model Q1000 Differential Scanning Calorimeter. The samples were placed in non-hermetic aluminum pans, equilibrated at 25°C under nitrogen flow (50 mL/min), and then heated from 25°C to 300°C at a ramp rate of 10°C/min. The melting point of the sample was taken as the onset of the melting peak of the DSC heat flow curve.

Thermogravimetric Analysis

Thermogravimetric analysis (TGA) was performed using a Q500 Thermogravimetric Analyzer from TA Instruments. The sample was placed in a platinum sample pan and heated from room temperature to 300°C at a heating rate of 10°C/min under nitrogen flow (50 mL/min). The weight of the solid sample as a function of temperature was recorded.

Dynamic Moisture Sorption

Dynamic Moisture Sorption (DVS) was performed using the Advantage 1.0 Dynamic Moisture Sorption Meter from Surface Measurement Systems. The temperature was set at 25°C, after drying for 60 minutes under the condition of humidity 0%RH (Relative Humidity), the hygroscopic characteristics of the samples were tested when the humidity changed from 0%-95%RH, and the humidity was changed from 95%-0%RH Dehumidification characteristics of the sample when changing; the humidity change step size is 5% RH, when the value of the mass change rate dm/dt is less than 0.002%, it is regarded as the balance balance, and the mass change rate within 5 minutes is less than 0.01%/min as the detection process. equilibration standard, the longest equilibration time is 2 hours. The isothermal adsorption/desorption water characteristics under the test conditions were recorded.

Preparation method of crystal form:

Suspension Equilibrium

Weigh the arsenic oxide sample into a container, add a certain amount of solvent, ultrasonicate for 5 minutes to disperse the sample evenly, wrap it in aluminum foil to block light, place it on a rotator, and start 360-degree rotation equilibrium at room temperature (20-25°C). After equilibrating for 7 days, a part of the suspension sample was taken for centrifugation, and the solid residue at the bottom was collected and evaporated to dryness at room temperature and characterized by XRPD. After equilibrating for 14 days, the remaining suspension samples were centrifuged, and the solid residues at the bottom were collected and evaporated to dryness at room temperature and characterized by XRPD.

Solution slow evaporation method

A sample of arsenic oxide of benzene was weighed and placed in a container, a small amount of solvent was added successively, and ultrasonication was performed until the solid was basically completely dissolved, and then filtered into a centrifuge tube using a 0.45 μm nylon filter membrane. The centrifuge tube was placed open after shading, and the solvent was naturally volatilized at room temperature (20-25° C.), and the precipitated solid sample was characterized by XRPD.

Solution rapid cooling method

A sample of arsenic oxide of benzene was weighed and placed in a container, a solvent was added, the container was heated in a 50° C. water bath and magnetically stirred, and the solid was completely dissolved and kept for 15 minutes. The solution was filtered through a 0.45 μm nylon filter while still hot, and the filtrate was transferred to a centrifuge tube. Immediately store the centrifuge tubes in a -20°C freezer overnight. The precipitated solid was collected by centrifugation and characterized by XRPD.

Solution slow cooling method

A sample of arsenic oxide of benzene was weighed and placed in a container, a solvent was added, the container was heated in a 50° C. water bath and magnetically stirred, and the solid was completely dissolved and kept for 15 minutes. The solution was filtered through a 0.45 μm nylon filter while still hot, and the filtrate was transferred to a centrifuge tube. Slowly cool down to room temperature (20-25°C) at a rate of 6°C/h, and store overnight. If there is no solid precipitation, the temperature is slowly lowered to 0-5°C at a rate of 6°C/h, and then transferred to a -20°C refrigerator for overnight storage. The precipitated solid was collected by centrifugation and characterized by XRPD.

Stability test:

A sample of arsenic oxide crystals was weighed and placed in a 20mL colorless transparent glass bottle, and the sample bottles were placed under the following conditions:

(1) High temperature: 60℃;

(2) High humidity: 92.5%RH;

(3) Lighting: 4500lux;

(4) Acceleration: 40℃, 75%RH;

Among them, sample vials under humidity conditions were sealed with tin foil and placed with holes, while other samples were placed with caps and tightly capped.

After standing for 2 weeks, it was taken out, the appearance was observed, and it was characterized by XRPD to investigate the physical stability of crystal forms I, II and III.

Benzene arsenic oxide crystal form I

PAO crystalline form I is a crystalline form without solvent or water, with birefringence phenomenon under polarized light microscope, and a flocculent or short rod-like crystal habit. The initial melting point of this crystal form was measured by DSC to be 105.14°C. According to TGA, the crystalline form loses 0.06% in weight from 26°C to 92°C, which may be a small amount of residual solvent or free water on the solid surface; from 92°C to 133°C, the weight loss is 0.21%, which may be a small amount of solvent or other easily contained in the powder pores. volatile components. The DVS test results show that the crystalline form has only 0.29% hygroscopic weight gain from 0%-80% RH, and less than 1.0% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity. In addition, the crystal form remained unchanged before and after DVS test by XRPD.

PAO crystal form I has good physical stability under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks, and there is no significant change in appearance and crystal form. By XRPD detection, PAO crystal form I is stable under the conditions of high temperature, high humidity, light and acceleration.

Example 1 Preparation of benzene arsenic oxide crystal form I: suspension equilibrium method

About 30 mg of benzene arsenic oxide samples were respectively weighed, solvent was added according to Table 1, and PAO crystal form I was prepared according to the aforementioned suspension equilibrium method. The Form I solid was collected and weighed to calculate the yield.

Table 1. Preparation of PAO Form I by Suspension Equilibrium Method

Numbering	solvent	Volume (mL)
1-1	water	0.8
1-2	methanol-water	2.4
1-3	acetone	0.5
1-4	Isopropyl acetate-acetone	0.5
1-5	Acetonitrile	0.5
1-6	4-Methyl-2-pentanone-acetonitrile	0.5
1-7	n-heptane	0.8
1-8	Methyl tert-butyl ether	0.5
1-9	Isopropyl ether-tetrahydrofuran	0.8

Example 2 Preparation of benzene arsenic oxide crystal form I: solution slow volatilization method

About 20 mg of phenylarsenic oxide samples were respectively weighed, solvent was added according to Table 2, and PAO crystal form I was prepared according to the slow volatilization method of the aforementioned solution. The Form I solid was collected and weighed to calculate the yield.

Table 2. Preparation of PAO crystal form I by solution slow volatilization

Numbering	solvent	Volume (mL)
2-1	Ethyl acetate	1

2-2	Dichloromethane	2
2-3	N,N-Dimethylformamide	1

The preparation of embodiment 3 benzene arsenic oxide crystal form I: solution rapid cooling method

About 20 mg of phenylarsenic oxide samples were weighed respectively, and a solvent was added according to Table 3, and the PAO crystal form I was prepared according to the aforementioned solution rapid cooling method. The Form I solid was collected and weighed to calculate the yield.

Table 3. Preparation of PAO crystal form I by solution rapid cooling method

Numbering	solvent	Volume (mL)
3-1	Isopropyl acetate-n-butanol	0.4
3-2	Acetonitrile	0.3
3-3	2-Methyltetrahydrofuran-ethyl acetate	0.3

Example 4 Preparation of benzene arsenic oxide crystal form I: solution slow cooling method

About 20 mg of phenylarsenic oxide samples were weighed respectively, and a solvent was added according to Table 4, and the PAO crystal form I was prepared according to the slow cooling method of the aforementioned solution. The Form I solid was collected and weighed to calculate the yield.

Table 4. Preparation of PAO crystal form I by solution rapid cooling method

Numbering	solvent	Volume (mL)
4-1	water	4
4-2	Acetone-acetonitrile	0.3

Example 5 XRPD characterization of benzene arsenic oxide crystal form I

The XRPD pattern of the arsenic oxide crystalline form I prepared according to the method described in Examples 1-4 was determined, as shown in Figure 1, at 2θ=8.02, 8.83, 9.38, 11.57, 17.92, 18.36, 19.89, 21.21, 22.62, 26.40 In addition, the XRPD pattern of benzene arsenic oxide crystal form I has secondary diffraction peaks at 2θ=21.68, 25.27, 29.50, 30.33 and 32.49. The error range of the 2θ value is ±0.2. After testing, the error range of the 2θ value can also be ±0.15.

A specific list of characteristic XRPD diffraction peaks derived from this spectrum is shown in Table 5.

Table 5. List of XRPD diffraction peaks in Figure 1

According to Bragg's law, the interplanar spacing d=λ/2sinθ in the above table.

Those skilled in the art should understand that these diffraction peaks do not represent the exhaustive situation of the diffraction peaks displayed by the crystal form I of benzene arsenic oxide. The 2Θ values of an X-ray powder diffraction pattern can vary slightly from machine to machine and with variations in sample preparation and from batch to batch, and the quoted values are not considered absolute. It should also be understood that the relative intensities of the peaks may vary with orientation effects and thus the intensities shown in the XRPD traces included in the present invention are exemplary and not intended for absolute comparison.

Example 6 Other characterizations of benzene arsenic oxide crystal form I

According to the aforementioned DCS, TGA and DVS analysis methods, the benzene arsenic oxide crystal form I was characterized respectively, and the spectra are shown in Figures 2-4, respectively.

The initial melting point of this crystal form was measured by DSC to be 105.14°C. According to TGA, the crystalline form loses 0.06% in weight from 26°C to 92°C, which may be a small amount of residual solvent or free water on the solid surface; from 92°C to 133°C, the weight loss is 0.21%, which may be a small amount of solvent or other easily contained in the powder pores. Volatile components; Form I is an anhydrous crystal form. The DVS test results show that the crystalline form has only 0.29% hygroscopic weight gain from 0%-80% RH, and less than 1.0% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity. In addition, the crystal form remained unchanged before and after DVS test by XRPD.

Embodiment 7 Stability test of benzene arsenic oxide crystal form I

Take an appropriate amount of phenylarsenic oxide crystal form I prepared by the method described in Examples 1-4, and test the physical stability of PAO crystal form I placed for 2 weeks under four conditions of high temperature, high humidity, light, and acceleration according to the aforementioned stability test method. sex. After 2 weeks, by XRPD detection, PAO crystal form I was stable under high temperature, high humidity, light, and accelerated conditions, as shown in Figure 5.

Benzene arsenic oxide crystal form II

PAO crystalline form II is a crystalline form without solvent or water, and has obvious birefringence phenomenon under polarized light microscope, showing granular or lamellar crystal habit. The initial melting point of this crystal form was measured by DSC to be 152.0°C. The weight loss of this crystal form from 28°C to 183°C measured by TGA was 0.2%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores. DVS test results show that the crystalline form has only 0.13% hygroscopic weight gain from 0%-80% RH, and less than 0.3% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity. In addition, the crystal form remained unchanged before and after DVS test by XRPD.

PAO crystal form II has good physical stability under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks, and there is no significant change in appearance and crystal form. According to XRPD detection, PAO crystal form II is stable under the conditions of high temperature, high humidity, light and acceleration.

Example 8 Preparation of benzene arsenic oxide crystal form II: solution slow volatilization method

About 20 mg of benzene arsenic oxide samples were weighed respectively, the solvent was added according to Table 6, and the PAO crystal form II was prepared according to the slow volatilization method of the solution described above. The Form II solid was collected and weighed to calculate the yield.

Table 6. Preparation of PAO crystal form I by solution slow volatilization

Numbering	solvent	Volume (mL)
6-1	methanol	1
6-2	isopropyl alcohol	4
6-3	n-Butanol	4
6-4	acetone	0.7
6-5	methyl ethyl ketone	0.8
6-6	isopropyl acetate	2.5
6-7	Acetonitrile	2.3
6-8	tetrahydrofuran	1
6-9	2-Methyltetrahydrofuran	3
6-10	Cyclohexane	4
6-11	isopropyl ether	4
6-12	1,4-Dioxane	1

Example 9 Preparation of benzene arsenic oxide crystal form II: suspension equilibrium method

About 30 mg of benzene arsenic oxide samples were respectively weighed, solvent was added according to Table 7, and PAO crystal form II was prepared according to the aforementioned suspension equilibrium method. The Form II solid was collected and weighed to calculate the yield.

Table 7. Preparation of PAO Form II by Suspension Equilibrium Method

Numbering	solvent	Volume (mL)
7-1	Methyl ethyl ketone-ethanol-cyclohexane-isopropanol	1.6

Example 10 Preparation of benzene arsenic oxide crystal form II: solution rapid cooling method

About 20 mg of benzene arsenic oxide samples were weighed respectively, the solvent was added according to Table 8, and the PAO crystal form II was prepared according to the aforementioned solution rapid cooling method. The Form II solid was collected and weighed to calculate the yield.

Table 8. Preparation of PAO crystal form II by solution rapid cooling method

Numbering	solvent	Volume (mL)
8-1	methanol	0.2
8-2	Ethanol	0.5
8-3	Isopropanol-n-Butanol	0.7
8-4	methyl ethyl ketone-cyclohexane	0.4
8-5	Dichloromethane	0.2
8-6	n-Butanol-Methanol	0.5

Example 11 Preparation of benzene arsenic oxide crystal form II: solution slow cooling method

About 20 mg of benzene arsenic oxide samples were weighed respectively, solvent was added according to Table 9, and PAO crystal form II was prepared according to the slow cooling method of the solution described above. The Form II solid was collected and weighed to calculate the yield.

Table 9. Preparation of PAO crystal form II by solution rapid cooling method

Numbering	solvent	Volume (mL)
9-1	Ethanol	0.2
9-2	isopropyl alcohol	1.2
9-3	Methyl ethyl ketone-isopropyl ether	0.2
9-4	Acetonitrile	0.3
9-5	Dichloromethane-methyl tert-butyl ether	0.3
9-6	4-Methyl-2-pentanone-isopropyl ether	0.4
9-7	n-heptane-cyclohexane	1.2
9-8	Methyl tert-butyl ether-isopropyl ether	0.8
9-9	1,4-Dioxane	0.4

Example 12 XRPD characterization of benzene arsenic oxide crystal form II

Determine the XRPD pattern of the benzene arsenic oxide crystal form II prepared according to the method described in Examples 8-11, as shown in Figure 6, at 2θ=8.48, 9.44, 14.63, 15.83, 17.28, 24.90, 25.18, 25.89, 26.20, 31.40 In addition, the XRPD pattern of benzene arsenic oxide crystal form II has secondary diffraction peaks at 2θ=12.38, 13.00, 19.90, 20.36 and 32.84. The error range of the 2θ value is ±0.2. After testing, the error range of the 2θ value can also be ±0.15.

A specific list of characteristic XRPD diffraction peaks derived from this spectrum is shown in Table 10.

Table 10. List of XRPD diffraction peaks in Figure 6

According to Bragg's law, the interplanar spacing d=λ/2sinθ in the above table.

Those skilled in the art should understand that these diffraction peaks do not represent the exhaustive situation of the diffraction peaks displayed by the crystal form II of benzene arsenic oxide. The 2Θ values of an X-ray powder diffraction pattern can vary slightly from machine to machine as well as with variations in sample preparation and from batch to batch, and the quoted values are not considered absolute. It should also be understood that the relative intensities of the peaks may vary with orientation effects, therefore the intensities shown in the XRPD traces included in the present invention are exemplary and not intended for absolute comparison.

Example 13 Other characterization of benzene arsenic oxide crystal form II

According to the aforementioned DCS, TGA and DVS analysis methods, the benzene arsenic oxide crystal form II prepared according to the methods described in Examples 8-11 was characterized, and the spectra were shown in Figures 7-9, respectively.

The initial melting point of this crystal form was measured by DSC to be 152.0°C. The weight loss of this crystal form from 28°C to 183°C measured by TGA was 0.2%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores. DVS test results show that the crystalline form has only 0.13% hygroscopic weight gain from 0%-80% RH, and less than 0.3% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity. In addition, the crystal form remained unchanged before and after DVS test by XRPD detection.

Example 14 Stability test of benzene arsenic oxide crystal form II

Take an appropriate amount of phenylarsenic oxide crystal form II prepared by the method described in Examples 8-11, and test the physical stability of PAO crystal form II under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks according to the aforementioned stability test method. sex. After 2 weeks, by XRPD detection, PAO crystal form II was stable under high temperature, high humidity, light, and accelerated conditions, as shown in Figure 10.

Benzene arsenic oxide crystal form III

PAO crystal form III is a crystal form without solvent or water, and has obvious birefringence phenomenon under polarized light microscope, showing a rod-like crystal habit. The initial melting point of this crystal form was measured by DSC to be 142.1°C. The weight loss of this crystal form from 27°C to 170°C measured by TGA was 0.5%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores. The DVS test results show that the crystalline form has only a hygroscopic weight gain of 0.29% from 0%-80% RH, and a hygroscopic weight gain of less than 0.8% from 0%-95% RH, indicating that the crystalline form has no hygroscopicity. In addition, the crystal form remained unchanged before and after DVS test by XRPD test.

PAO crystal form III has good physical stability under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks, and there is no significant change in appearance and crystal form. According to XRPD detection, PAO crystal form III is stable under the conditions of high temperature, high humidity, light and acceleration.

Example 15 Preparation of benzene arsenic oxide crystal form III: suspension equilibrium method

About 50 mg of phenylarsenic oxide samples were respectively weighed, solvent was added according to Table 11, ultrasonicated for 5 minutes to disperse the samples evenly, wrapped in aluminum foil to block light, and then beaten in a 50°C water bath for 24 hours. The Form III solid was collected by filtration or centrifugation, and the yield was calculated by weighing.

Table 11. Preparation of PAO Form III by Suspension Equilibrium Method

Numbering	solvent	Volume (mL)
11-1	acetone	1
11-2	Ethyl acetate	1

Example 16 Preparation of benzene arsenic oxide crystal form III: solution rapid cooling method

About 20 mg of benzene arsenic oxide samples were respectively weighed, solvent was added according to Table 12, and PAO crystal form III was prepared according to the aforementioned solution rapid cooling method. The Form III solid was collected and weighed to calculate the yield.

Table 12. Preparation of PAO crystal form III by solution rapid cooling method

Numbering	solvent	Volume (mL)
12-1	Toluene	0.3

Example 17 XRPD characterization of benzene arsenic oxide crystal form III

Determine the XRPD pattern of the phenylarsenic oxide crystal form III prepared according to the method described in Examples 15-17, as shown in Figure 11, at 2θ=8.39, 9.50, 16.04, 16.56, 18.06, 19.11, 19.44, 23.85, 25.25, 25.70 There are diffraction peaks at 31.74 and 31.74; in addition, the XRPD pattern of benzene arsenic oxide crystal form III is secondary at 2θ=12.55, 13.85, 14.55, 15.14, 20.68, 22.06, 29.23, 32.10, 33.15, 33.69, 34.51, 36.75, 39.00 Diffraction peaks. The error range of the 2θ value is ±0.2. After testing, the error range of the 2θ value can also be ±0.15.

A specific list of characteristic XRPD diffraction peaks derived from this spectrum is shown in Table 13.

Table 13. List of XRPD diffraction peaks in Figure 11

According to Bragg's law, the interplanar spacing d=λ/2sinθ in the above table.

Those skilled in the art should understand that these diffraction peaks do not represent the exhaustive situation of the diffraction peaks displayed by the crystal form III of phenylarsenic oxide. The 2Θ values of an X-ray powder diffraction pattern can vary slightly from machine to machine and with variations in sample preparation and from batch to batch, and the quoted values are not considered absolute. It should also be understood that the relative intensities of the peaks may vary with orientation effects, therefore the intensities shown in the XRPD traces included in the present invention are exemplary and not intended for absolute comparison.

Example 19 Other characterization of benzene arsenic oxide crystal form III

According to the aforementioned DCS, TGA and DVS analysis methods, the phenylarsenic oxide crystal form III prepared according to the methods described in Examples 15-17 was characterized, and the spectra were shown in Figures 12-14, respectively.

The initial melting point of this crystal form was measured by DSC to be 142.1°C. The weight loss of this crystal form from 27°C to 170°C measured by TGA was 0.5%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores. The DVS test results show that the crystalline form has only a hygroscopic weight gain of 0.29% from 0%-80% RH, and a hygroscopic weight gain of less than 0.8% from 0%-95% RH, indicating that the crystalline form has no hygroscopicity. In addition, the crystal form remained unchanged before and after DVS test by XRPD test.

Example 20 Stability test of benzene arsenic oxide crystal form III

Take an appropriate amount of phenylarsenic oxide crystal form III prepared by the method described in Examples 15-17, and test the physical stability of PAO crystal form III under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks according to the aforementioned stability test method. sex. After 2 weeks, XRPD detection showed that PAO crystal form III was stable under high temperature, high humidity, light, and accelerated conditions, as shown in Figure 15.

To sum up, the crystal form I, crystal form II and crystal form III of benzene arsenic oxide can remain stable under high temperature, high humidity, light and accelerated conditions. A stable crystal form has advantages in the production of pharmaceutical formulations. Since arsenic oxide crystal form I, crystal form II and crystal form III have excellent high temperature stability, high humidity stability and light stability, they can remain stable during the drug processing of various solid dosage forms, and it can be determined that the final obtained The crystal form of the active ingredient in the drug can ensure the known bioavailability, and there will be no difference in efficacy due to crystal form transformation. Among them, the test results of the crystal forms of benzene arsenic oxide crystal form I, crystal form II and crystal form III are shown in Table 14. In addition, three different crystalline forms were dissolved in different types of vegetable oils and the solubility was compared.

Table 14. Test results of three crystal forms

Example 21 Application of phenylarsenic oxide crystal forms I, II and III in drug preparation and disease treatment

The phenylarsenic oxide crystal form I, crystal form II and crystal form III of the present invention can be prepared into common solid dosage forms such as tablets, powders, granules, capsules and the like after being pulverized and combined with pharmaceutical excipients.

Through animal experiments and/or cell in vitro experiments, the arsenic oxide crystal form I, crystal form II and crystal form III of the present invention have certain inhibitory and/or therapeutic effects on Alzheimer's disease.

Example 22 Solubility test of PAO crystal form II in MCT

The term "medium-chain triglycerides" (MCT or Medium-chain Triglycerides) as used herein refers to fatty acids (including one or more of caproic acid, caprylic acid, capric acid and lauric acid) having a length of 6 to 12 carbon atoms species) of triglycerides. Medium chain triglycerides have a low freezing point and are liquid at room temperature with low viscosity. In some embodiments, the medium chain triglycerides described herein are extracted from the dry hard part of the endosperm of coconut (eg, Cocos nucifera L.) or oil palm (eg, Elaeis guineenis Jacq). Typical medium chain triglycerides refer to saturated caprylic triglycerides or saturated capric triglycerides or saturated caprylic-capric mixed triglycerides. In some embodiments, the medium chain triglycerides described herein meet generally recognized pharmacopeia (eg, US Pharmacopoeia, Chinese Pharmacopoeia, or European Pharmacopoeia) standards for medium chain triglycerides. In some embodiments, the medium chain triglycerides described herein are of the type

812N medium chain triglycerides.

Example 23 Kinetic research experiment of PAO crystal form II in animals

23.1 In vivo kinetics study of oral MCT formulations of PAO crystal form II in monkeys

Two groups of monkeys were selected, one male and one male in each group. The first group (male 101 and female 102) were orally administered with PAO, the vehicle was MCT, and the dose was 0.3 mg/kg/day for 2 consecutive weeks. Blood was collected at 0.5, 1, 2, 4, 8, 12, 24, and 48 hours after the last day of dosing, and the concentration of the compound in the blood (whole blood, not plasma) was measured.

The second group (male 301 and female 302) were orally administered with PAO crystal form II, the same vehicle was MCT, and the dose was 0.3 mg/kg. Blood was collected at 0.5, 1, 2, 4, 8, 12, 24, and 48 hours after administration, and the concentration of the compound in whole blood was also measured. After 5 days of drug withdrawal, PAO was orally administered, the same vehicle was MCT, and the dose was 0.6 mg/kg. Blood was collected at 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after administration, and the concentration of the compound in the blood was measured.

Table 15. Plasma concentrations at different times

Table 16.0.3mpk pharmacokinetic parameters

animal ID	101	102	average value	animal ID	301	302	average value
Rsq_adj	ND	ND	--	Rsq_adj	ND	0.877	--
Points for T 1/2	0.00	0.00	0.00	Points for T 1/2	0.00	5.00	ND
Cmax (ng/mL)	172	141	157	Cmax (ng/mL)	75.9	50.7	63.3
Tmax (h)	4.00	4.00	4.00	Tmax (h)	12.0	2.00	7.00
T 1/2 (h)	ND	ND	ND	T 1/2 (h)	ND	38.6	ND
T last (h)	48.0	48.0	48.0	T last (h)	48.0	48.0	48.0
AUC 0-last (ng·h/mL)	3760	4500	4130	AUC 0-last (ng·h/mL)	1880	1554	1717
AUC 0-inf (ng.h/mL)	ND	ND	ND	AUC 0-inf (ng.h/mL)	ND	2823	ND
MRT 0-last (h)	26.1	24.8	25.4	MRT 0-last (h)	20.8	20.7	20.8
MRT 0-inf (h)	ND	ND	ND	MRT 0-inf (h)	ND	58.0	ND
AUC Extra (%)	ND	ND	ND	AUC Extra (%)	ND	45.0	ND
AUMC Extra (%)	ND	ND	ND	AUMC Extra (%)	ND	80.4	ND

Table 17.0.6mpk pharmacokinetic parameters

animal ID	301	302	average value
Rsq_adj	0.883	0.897	--
Points for T 1/2	6.00	6.00	6.00
Cmax (ng/mL)	126	144	135
Tmax (h)	1.00	1.00	1.00
T 1/2 (h)	23.5	29.9	26.7
T last (h)	48.0	48.0	48.0
AUC 0-last (ng·h/mL)	2807	3796	3302
AUC 0-inf (ng.h/mL)	3925	6004	4964
MRT 0-last (h)	18.5	19.7	19.1
MRT 0-inf (h)	36.6	46.0	41.3

AUC Extra (%)	28.5	36.8	32.6
AUMC Extra (%)	63.8	72.9	68.4

Remarks: ND: not measured (due to insufficient definition of terminal elimination phase, parameter not measured)

BQL: Below the lower limit of quantification (LLOQ)

If the adjusted rsq (linear regression coefficient of the final phase concentration value) is less than 0.9, then T _1/2 may not be estimated accurately.

If %AUCExtra > 20%, AUC0-inf, Cl, MRT0-inf and Vdss may not be estimated accurately.

If %AUMCExtra > 20%, MRT0-inf and Vdss may not be estimated accurately.

If the adjusted linear regression coefficient for the final phase concentration value is less than 0.9, then T _1/2 may not be estimated accurately.

Analysis: After a single dose of MCT preparation of PAO in monkeys, PAO can be absorbed into the blood, and the plasma concentration reaches the highest within 4 hours; the half-life of PAO in the blood is long, about 26.7 hours; Can maintain a higher blood pressure concentration. Taken together, it is shown that MCT formulations of PAO can be used to deliver PAO orally. The MCT preparation of PAO was orally administered to monkeys daily at a dose of 0.3 mg/kg/day. After 2 consecutive weeks, the average exposure of PAO in blood (AUC _0-last = 4130 ng·h/mL) was about the same as that of a single oral dose (AUC 0-last = 4130 ng·h/mL). _0-last = 1717ng·h/mL) 2.4 times, indicating that repeated administration will lead to drug accumulation, suggesting that continuous daily oral medication for 2 weeks or within 2 weeks, medication should be suspended for 1-2 days.

23.2 In vivo kinetics study of sesame oil preparation of PAO crystal form II and intravenous injection of PAO in monkeys

The fatty acids in MCT are mainly medium-chain saturated fatty acids, while the fatty acids in sesame oil are mainly long-chain unsaturated fatty acids. There is a significant difference between the two, and the long-chain fatty acids are mainly absorbed through the lymphatic vessels in the intestine, while the medium-chain fatty acids are mainly absorbed through the intestine. mucosal cell uptake. Therefore, we examined the kinetics of an oral sesame oil formulation of PAO in monkeys and compared it with that of intravenous PAO.

Two groups of monkeys were selected, both male. The first group (C1001 and C1002) was administered PAO by iv injection, the vehicle was 1% DMSO, the actual dose was 0.118 mg/kg (nominal dose: 0.100 mg/kg), a single dose; the second group (C2001 and C2002) Oral administration of PAO, the vehicle is sesame oil, the actual dose is 0.168 mg/kg (nominal dose: 0.200 mg/kg), and it is also a single dose. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after administration, and the concentration of the compound in blood (whole blood, not plasma) was measured.

The results are shown in Table 18:

Table 18: Results of in vivo kinetic studies in monkeys

Remarks: ND: not measured (due to insufficient definition of terminal elimination phase, parameter not measured)

BQL: Below the lower limit of quantification (LLOQ)

If the adjusted rsq (linear regression coefficient of the final phase concentration value) is less than 0.9, then T _1/2 may not be estimated accurately.

If %AUC _Extra >20%, AUC _0-inf , Cl, MRT _0-inf and Vd _ss may not be estimated accurately.

MRT _0-inf and Vd _ss may not be estimated accurately if %AUMC _Extra >20%.

If the adjusted linear regression coefficient for the final phase concentration value is less than 0.9, then T _1/2 may not be estimated accurately.

a: Calculate bioavailability (%) using AUC0 _-inf (%AUC _Extra <20%) or AUC0 _-last (%AUC _Extra >20%) at nominal dose

Analysis: After a single oral administration of the sesame oil preparation of PAO (0.168), PAO can also be absorbed into the blood, PAO can also be absorbed into the blood, and the blood concentration reaches the highest within 4 hours; the half-life of PAO in the blood is about 27.5 hours; the average exposure of PAO in blood (AUC _0-last = 826 ng·h/mL) is about the average exposure of 0.3 mg/kg of the MCT preparation of a single oral dose of PAO (AUC _0-last = 1717 ng·h) /mL), 0.48 times the average exposure of 0.6 mg/kg (AUC _0-last = 4130 ng·h/mL) 0.2 times. It shows that the in vivo kinetics and bioavailability of oral sesame oil formulations of PAO and MCT formulations are comparable .

24.3 In vivo kinetics study of oral MCT formulations of PAO crystal form II in beagle dogs

Both groups of beagle dogs were male. Group 1 (D1001 and D1002), PAO administered by iv injection, vehicle is 1% DMSO, actual dose 0.101mg/kg (nominal dose: 0.100mg/kg) single dose; Group 2 (D2001 and D2002) Oral administration of PAO, the vehicle is sesame oil, the actual dose is 0.169 mg/kg (nominal dose: 0.200 mg/kg), and it is also a single dose. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after administration, and the concentration of the compound in blood (whole blood, not plasma) was measured.

The results are shown in Table 19:

Table 19. Results of in vivo kinetic studies in beagle dogs

Remarks: ND: not measured (due to insufficient definition of terminal elimination phase, parameter not measured)

BQL: Below the lower limit of quantification (LLOQ)

If the adjusted rsq (linear regression coefficient of the final phase concentration value) is less than 0.9, then T _1/2 may not be estimated accurately.

If %AUC _Extra >20%, AUC _0-inf , Cl, MRT _0-inf and Vd _ss may not be estimated accurately.

MRT _0-inf and Vd _ss may not be estimated accurately if %AUMC _Extra >20%.

If the adjusted linear regression coefficient for the final phase concentration value is less than 0.9, then T _1/2 may not be estimated accurately.

a: Calculate bioavailability (%) using AUC0 _-inf (%AUC _Extra <20%) or AUC0 _-last (%AUC _Extra >20%) at nominal dose

Analysis: After a single oral administration of the sesame oil preparation of PAO in beagle dogs, the blood concentration reached the highest within 4 hours, and the bioavailability was similar, about 15%. However, the exposure to PAO in beagle blood was about a quarter of the exposure in monkey blood. It indicated that the bioavailability of lipid preparations of PAO in different animal species was similar, but the exposures were quite different.

23.4 In vivo kinetic studies of oral DMSO and MCT formulations of PAO crystal form II in mice

To compare the difference between the oral formulation of DMSO and the oral formulation of MCT, an in vivo kinetic study in mice was performed. The male mice were divided into two groups with 3 mice in each group. One group was orally administered with PAO (M01, M02 and M03), the vehicle was a 1% DMSO aqueous solution, and the actual dose was 0.0913 mg/kg (nominal dose: 0.100 mg/kg). kg); another group was orally administered the MCT formulation of PAO (N01, N02 and N03), the actual dose was 0.107 mg/kg (nominal dose: 0.100 mg/kg). Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose and the concentration of the compound in blood (whole blood, not plasma) was measured.

The results are shown in Table 20:

Table 20. Results of in vivo kinetic studies in mice of 1% DMSO formulation of oral PAO (dose: 0.0913 mg/kg)

Remarks: ND: not measured (due to insufficient definition of terminal elimination phase, parameter not measured)

BQL: Below the lower limit of quantification (LLOQ)

If the adjusted rsq (linear regression coefficient of the final phase concentration value) is less than 0.9, then T _1/2 may not be estimated accurately.

If %AUC _Extra >20%, AUC _0-inf , Cl, MRT _0-inf and Vd _ss may not be estimated accurately.

MRT _0-inf and Vd _ss may not be estimated accurately if %AUMC _Extra >20%.

If the adjusted linear regression coefficient for the final phase concentration value is less than 0.9, then T _1/2 may not be estimated accurately.

Table 21. Results of in vivo kinetic studies in mice of oral MCT formulation of PAO (0.107 mg/kg)

Remarks: ND: not measured (due to insufficient definition of terminal elimination phase, parameter not measured)

BQL: Below the lower limit of quantification (LLOQ)

If the adjusted rsq (linear regression coefficient of the final phase concentration value) is less than 0.9, then T _1/2 may not be estimated accurately.

If %AUC _Extra >20%, AUC _0-inf , Cl, MRT _0-inf and Vd _ss may not be estimated accurately.

MRT _0-inf and Vd _ss may not be estimated accurately if %AUMC _Extra >20%.

If the adjusted linear regression coefficient for the final phase concentration value is less than 0.9, then T _1/2 may not be estimated accurately.

The results show that although the MCT formulation of PAO crystal form II has a sustained release phenomenon in simulated gastric juice, the bioavailability of PAO delivered by MCT formulation is significantly higher than that of PAO delivered by an aqueous solution of co-solvent DMSO. Therefore, on the one hand, the lipid preparation of PAO can release PAO slowly in gastric juice and reduce the stimulation of PAO to gastric mucosa; on the other hand, it can increase the bioavailability of PAO.

Example 24: Toxicity study experiment of different formulations of PAO crystal form II in animals

In order to compare the toxicity of PAO's MCT preparation and PAO's 0.1% DMSO aqueous solution in animals, 20 male and female 10-week-old ICR mice were taken and divided into 4 groups. MCT formulations of PAO or PAO in 0.1% DMSO in water (v/v) were administered for 46 days (mice are grouped in Table 22), and dead mice were weighed daily and recorded.

Table 22 Grouping of mice

After 46 days of continuous dosing, all female mice survived. The average body weights of the two groups of female mice that received the MCT preparation of PAO at 0.75 mg/kg/day and 0.1% DMSO in water slowly increased slowly, and there was almost no difference between the two groups at the completion of dosing (30.6 g vs. 30.2 g); according to 1.5 The average body weight of female mice receiving MCT preparation of PAO orally at mg/kg/day also increased slowly to 32.9 g, but the average body weight of mice receiving oral administration of PAO in 0.1% DMSO water solution decreased significantly after the second week, and finally decreased to 32.9 g. 24.4 grams. As for male mice, every mouse that was orally administered with MCT preparation of PAO at 0.75 mg/kg/day survived, and the weight of each mouse increased slowly, but the weight changes of the other three groups of mice had no obvious regularity; One of the 5 mice that received 1.5 mg/kg/day orally administered PAO in MCT formulation died in the second week of administration; one of the 5 mice that received 0.75 mg/kg/day orally administered PAO in 0.1% DMSO aqueous solution died. At the second week of administration, two of the five mice that received PAO orally in 0.1% DMSO in water at 1.5 mg/kg/day died at the second and sixth week of administration, respectively.

These results show that although the bioavailability of PAO delivered by the MCT formulation is significantly higher than that of PAO delivered using an aqueous solution of the co-solvent DMSO, the MCT formulation of PAO produces significantly less toxicity in vivo.

It will be apparent to those skilled in the art that although specific embodiments of the invention are described herein for illustrative purposes, various modifications can be made therein without departing from the spirit and scope of the invention. Therefore, the specific descriptions and examples of the present invention should not be construed as limiting the scope of the present invention. The invention is limited only by the appended claims. All documents cited in this application are incorporated by reference in their entirety.

Claims (25)

1. Form I of the compound represented by formula (I),

   

   It is characterized in that, the XRPD pattern of the crystal form has diffraction peaks at the following 2θ angles: 8.02°±0.2°, 8.83°±0.2°, 9.38°±0.2°, 11.57°±0.2°, 17.92°±0.2°, 18.36°±0.2°, 19.89°±0.2°, 21.21°±0.2°, 22.62°±0.2°, 26.40°±0.2°.
2. Crystal form I as claimed in claim 1, is characterized in that,

   The XRPD pattern of the crystalline form has diffraction peaks at the following 2θ angles: 8.02°±0.2°, 8.83°±0.2°, 9.38°±0.2°, 11.57°±0.2°, 17.92°±0.2°, 18.36°±0.2 °, 19.89°±0.2°, 21.21°±0.2°, 21.68°±0.2°, 22.62°±0.2°, 25.27°±0.2°, 26.40°±0.2°, 29.50°±0.2°, 30.33°±0.2°, 32.49°±0.2°.
3. The crystal form I of claim 1, wherein the XRPD pattern of the crystal form is substantially as shown in FIG. 1 .
4. The crystalline form I according to claim 1, wherein the crystalline form I further has at least one of the following features: substantially the same DSC spectrum as FIG. 2; or substantially the same TGA spectrum as FIG. 3; or a dynamic moisture adsorption profile substantially the same as in Figure 4.
5. The preparation method of crystal form I according to any one of claims 1 to 4, characterized in that, comprising the following steps:

   (1) phenylarsenic oxide is added to the solvent to obtain a suspension, which is suspended at room temperature;

   (2) Collect the solids in the suspension, namely the benzene arsenic oxide crystal form I solid.

   Wherein, the solvent is selected from water, methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, 4-methyl-2-pentanone, n-heptane, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran and any two or more mixtures thereof.

   Preferably, the solvent is water, methanol-water, acetone, isopropyl acetate-acetone, acetonitrile, 4-methyl-2-pentanone-acetonitrile, n-heptane, methyl tert-butyl ether, or isopropyl Ether-tetrahydrofuran.
6. The preparation method of phenylarsenic oxide crystal form I according to any one of claims 1 to 4, characterized in that, comprising the following steps:

   (1) phenylarsenic oxide is added to the solvent to obtain a solution;

   (2) at room temperature, the solvent of the solution is naturally volatilized, and the solid is collected, which is the benzene arsenic oxide crystal form I solid,

   Wherein, the solvent is selected from the group consisting of ethyl acetate, dichloromethane, N,N-dimethylformamide or n-heptane and a mixture of any two or more thereof.
7. The preparation method of phenylarsenic oxide crystal form I according to any one of claims 1 to 4, characterized in that, comprising the following steps:

   (1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

   (2) the hot solution is transferred to the low temperature environment for cooling, and the solid that separates out is collected, which is the benzene arsenic oxide crystal form I solid,

   Wherein, the solvent is selected from isopropanol, acetone, ethyl acetate, isopropyl acetate, n-butanol, acetonitrile, 4-methyl-2-pentanone, n-heptane, cyclohexane, methyl tert-butyl The group consisting of base ether, isopropyl ether, dichloromethane, 1,4-dioxane or 2-methyltetrahydrofuran and mixtures of any two or more thereof;

   Preferably, the solvent is isopropyl acetate, acetonitrile or 2-methyltetrahydrofuran-ethyl acetate.
8. The preparation method of phenylarsenic oxide crystal form I according to any one of claims 1 to 4, characterized in that, comprising the following steps:

   (1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

   (2) the temperature of the hot solution is slowly cooled in a controlled manner, until the solid is separated out, and the separated solid is collected, which is the phenylarsenic oxide crystal form I solid,

   Wherein, the solvent is selected from the group consisting of water, acetone, isopropyl acetate, cyclohexane, acetonitrile, ethyl acetate and any two or more mixtures thereof;

   Preferably the solvent is water or acetone-acetonitrile.
9. Form II of the compound represented by formula (I),

   

   It is characterized in that, the XRPD pattern of the crystal form has diffraction peaks at the following 2θ angles: 8.48°±0.2°, 9.44°±0.2°, 14.63°±0.2°, 15.83°±0.2°, 17.28°±0.2°, 24.90°±0.2°, 25.18°±0.2°, 25.89°±0.2°, 26.20°±0.2°, 31.40°±0.2°.
10. The crystal form II according to claim 9, characterized in that,

    The XRPD pattern of the crystalline form has diffraction peaks at the following 2θ angles: 8.48°±0.2°, 9.44°±0.2°, 12.38°±0.2°, 13.00°±0.2°, 14.63°±0.2°, 15.83°±0.2 °, 17.28°±0.2°, 19.90°±0.2°, 20.36°±0.2°, 24.90°±0.2°, 25.18°±0.2°, 25.89°±0.2°, 26.20°±0.2°, 31.40°±0.2°, 32.84°±0.2°.
11. The crystal form II of claim 9 , wherein the XRPD pattern of the crystal form is substantially as shown in FIG. 6 .
12. The crystalline form II of claim 9, wherein the crystalline form II further has at least one of the following features: substantially the same DSC pattern as FIG. 7; substantially the same TGA pattern as FIG. 8; or Essentially the same dynamic moisture adsorption profile as in Figure 9.
13. The preparation method of crystal form II according to any one of claims 9 to 12, characterized in that, comprising the following steps:

    (1) phenylarsenic oxide is added to the solvent to obtain a solution;

    (2) at room temperature, the solvent of the solution is naturally volatilized, and the solid is collected, which is the benzene arsenic oxide crystal form II solid,

    Wherein, the solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclohexane, isopropyl ether, 1,4- The group consisting of dioxane, toluene, n-heptane and mixtures of any two or more thereof.
14. The preparation method of crystal form II according to any one of claims 9 to 12, characterized in that, comprising the following steps:

    (1) phenylarsenic oxide is added to the solvent to obtain a suspension, which is stirred and suspended at room temperature;

    (2) The solid in the suspension is collected, which is the benzene arsenic oxide crystal form II solid.

    Wherein, the solvent is the group formed by methyl ethyl ketone, ethanol, cyclohexane, isopropanol, ethyl acetate and any two or more mixtures thereof;

    Preferably, the solvent is methyl ethyl ketone-ethanol-cyclohexane-isopropanol.
15. The preparation method of crystal form II according to any one of claims 9 to 12, characterized in that, comprising the following steps:

    (1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

    (2) transfer the hot solution to a low temperature environment for cooling, and collect the precipitated solid, which is the benzene arsenic oxide crystal form II solid,

    Wherein, the solvent is selected from methanol, ethanol, isopropanol, n-butanol, methyl ethyl ketone, cyclohexane, dichloromethane, acetone, ethyl acetate, 4-methyl-2-pentanone, cyclohexane, methyl ethyl ketone The group consisting of tert-butyl ether, isopropyl ether, 1,4-dioxane and mixtures of any two or more thereof;

    Preferably, the solvent is methanol, ethanol, isopropanol-n-butanol, methyl ethyl ketone-cyclohexane, dichloromethane, or n-butanol-methanol.
16. The preparation method of crystal form II according to any one of claims 9 to 12, characterized in that, comprising the following steps:

    (1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

    (2) the hot solution is slowly cooled in a controlled manner, until the solid is separated out, and the separated solid is collected, which is the phenylarsenic oxide crystal form II solid,

    Wherein, the solvent is selected from ethanol, isopropanol, methyl ethyl ketone, isopropyl ether, acetonitrile, dichloromethane, methyl tert-butyl ether, 4-methyl-2-pentanone, n-heptane, 1,4- The group consisting of dioxane, acetone, isopropyl acetate, cyclohexane, dioxane and any two or more mixtures thereof;

    Preferably, the solvent is ethanol, isopropanol, methyl ethyl ketone-isopropyl ether, acetonitrile, dichloromethane-methyl tert-butyl ether, 4-methyl-2-pentanone-isopropyl ether, n-heptane- Cyclohexane, methyl tert-butyl ether-isopropyl ether, or 1,4-dioxane.
17. Crystal form III of the compound represented by formula (I),

    

    It is characterized in that, the XRPD pattern of the crystal form has diffraction peaks at the following 2θ angles: 8.39°±0.2°, 9.50°±0.2°, 16.04°±0.2°, 16.56°±0.2°, 18.06°±0.2°, 19.11°±0.2°, 19.44°±0.2°, 23.85°±0.2°, 25.25°±0.2°, 25.70°±0.2°, 31.74°±0.2°.
18. The crystal form III of claim 17, wherein:

    The XRPD pattern of the crystalline form has diffraction peaks at the following 2θ angles: 8.39°±0.2°, 9.50°±0.2°, 12.55°±0.2°, 13.85°±0.2°, 14.55°±0.2°, 15.14°±0.2 °, 16.04°±0.2°, 16.56°±0.2°, 18.06°±0.2°, 19.11°±0.2°, 19.44°±0.2°, 20.68°±0.2°, 22.06°±0.2°, 23.85°±0.2°, 25.25°±0.2°, 25.70°±0.2°, 29.23°±0.2°, 32.10°±0.2°, 33.15°±0.2°, 33.69°±0.2°, 34.51°±0.2°, 36.75°±0.2°, 39.00° ±0.2°, 31.74°±0.2°.
19. The crystal form III of claim 17 , wherein the XRPD pattern of the crystal form is substantially as shown in FIG. 11 .
20. The crystalline form III according to claim 17, wherein the crystalline form III further has at least one of the following features: substantially the same DSC pattern as in FIG. 12; substantially the same TGA pattern as in FIG. 13; or Essentially the same dynamic moisture adsorption profile as in Figure 14.
21. The preparation method of crystal form III according to any one of claims 17 to 20, characterized in that, comprising the following steps:

    (1) phenylarsenic oxide is added to the solvent to obtain a solution;

    (2) at room temperature, the solvent of the solution is naturally volatilized, and the solid is collected, which is the phenylarsenic oxide crystal form III solid,

    Wherein, the solvent is toluene.
22. The preparation method of crystal form III according to any one of claims 17 to 20, characterized in that, comprising the following steps:

    (1) phenylarsenic oxide is added to the solvent to obtain a suspension, which is stirred and suspended under heating;

    (2) Collecting the solid in the suspension, that is, the benzene arsenic oxide crystal form III solid.

    In the above-mentioned preparation method of phenylarsenic oxide crystal form III, the solvent is the group consisting of toluene, acetone, ethyl acetate and any two or more mixtures thereof;

    Preferably, the solvent is acetone or ethyl acetate.
23. The preparation method of phenylarsenic oxide crystal form III according to any one of claims 17 to 20, characterized in that, comprising the following steps:

    (1) phenylarsenic oxide is added to the solvent and heated to obtain a solution;

    (2) transfer the hot solution to a low temperature environment for cooling, and collect the precipitated solid, which is the phenylarsenic oxide crystal form III solid,

    Wherein, the solvent is toluene.
24. A pharmaceutical composition, comprising the crystal or its combination as described in any one of claims 1-4, 9-12, 17-20, and a pharmaceutically acceptable adjuvant, preferably, the pharmaceutically acceptable Accepted excipients are pharmaceutically acceptable carriers, diluents and/or excipients.
25. A crystal form according to any one of claims 1-4, 9-12, 17-20 or a combination thereof or the use of the pharmaceutical composition according to claim 24 in the preparation of a medicine, preferably, the medicine For the treatment or prevention of Alzheimer's disease in patients.

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